COPPER-DEPENDENT INFLAMMATION AND NUCLEAR FACTOR-KAPPA-B ACTIVATION BY PARTICULATE AIR-POLLUTION

Particulate air pollution causes increased cardiopulmonary morbidity a nd mortality, but the chemical determinants responsible for its biolog ic effects are not understood. We studied the effect of total suspende d particulates collected in Prove, Utah, an area when an increase in r espiratory symptoms in relation to levels of particulate pollution has been well documented. Prove particulates caused cytokine-induced neut rophil chemoattractant-dependent inflammation of rat lungs. Prove part iculates stimulated interleukin-6 (IL-6) and IL-8 production, increase d IL-8 messenger RNA (mRNA) and enhanced expression of intercellular a dhesion molecule-1 (ICAM-1) in cultured BEAS-2B cells, and stimulated IL-8 secretion in primary cultures of human bronchial epithelium. Cyto kine secretion was preceded by activation of the transcription factor nuclear factor-kappa B (NF-kappa B) and was reduced by treatment of cu ltures with superoxide dismutase, deferoxamine, or N-acetylcysteine. T hese biologic effects were replicated by culturing BEAS cells with qua ntities of Cu2+ found in Prove extract. IL-8 secretion by BEAS cells c ould be modified by addition of normal constituents of airway lining f luid to the culture medium. Mucin significantly reduced IL-8 secretion , and ceruloplasmin significantly increased IL-8 secretion and activat ion of NF-kappa B. These findings suggest that copper ions may cause s ome of the biologic effects of inhaled particulate air pollution in th e Prove region of the United States, and may provide an explanation fo r the sensitivity of asthmatic individuals to Prove particulates that has been observed in epidemiologic studies.